The extent and cost of drug addiction and neuronal injury is staggering. In the National Drug Threat Assessment 2006 published in January 2006 the estimated economic cost of drug abuse to the United States was $180.9 billion. Of this, $97.7 billion was due to non-alcohol related drug abuse. In 1995 the White House Office of National Drug Control Policy estimated that Americans spent $57.3 billion on drugs of abuse. In 1999, about 14.8 million Americans were current users of illicit drugs with an estimated 3.5 million that were dependent on illicit drugs. The economic burden due to illicit drug use is due to both social issues as well as medical problems associated with drug addiction including brain injury and stroke. To address the problem of brain and nervous system disorders investigators have focused attention on describing cell injury mechanisms. However, discovery of cell survival strategies could have profound impact on the treatment of brain injury and loss of function and is an area that has not yet been rigorously investigated. Neuronal preconditioning is a phenomenon in which tissue is severely stressed but allowed to recover. Subsequently, the tissue is remarkably resistant to further toxic events. Preconditioning is dependent on new gene transcription and protein expression. In the last grant we developed a novel screen and identified 31 putative neuroprotective genes and over a thousand late response activity dependent genes. Several neuroprotective genes were known. We characterized several unknown or novel genes. We focused our attention on an unknown gene we named Iduna and a poorly studied transcription factor NF1-A. Expression of both Iduna and NF1-A are regulated by a NMDA and nitric oxide (NO) dependent signaling pathway and expression of either gene provides neuroprotection. We have also identified a novel non-coding RNA regulated by NO that is critically important for neuronal survival. This non-coding RNA we have termed NO inducible gene 17 (NOIG17). We believe NOIG17 may code for a microRNA cassette. Recently microRNA's have been discovered to play a critical role in neuroplasticity, but to date there are no known neuroprotective microRNA's. This proposal will focus on understanding NO signaling resulting in neuroprotection. The long range goal of this work will be to identify targets that can be developed in the future to ease the burden of individuals suffering brain injury due to drug abuse.